Approximately 1.6 million people live with HIV/AIDS in North America; 34 million people worldwide. The HIV/AIDS epidemic is caused by a rapidly replicating retrovirus that undergoes multiple mutations, making it extremely challenging to successfully treat. Millions of patients have strains of HIV that resist one or more of the currenty available HIV therapies. Progress has been made in the global fight against HIV/AIDS, but the epidemic continues to devastate the US and the rest of the world with some 51,000 and 2.5 million new HIV infections each year, respectively. To overcome HIV's drug resistance, new, validated targets and novel therapeutics are urgently needed. Sirga has developed a novel approach that uniquely interferes with an interaction between human (the host) cells and HIV that is absolutely essential for viral replication and propagation. Sirga expects this approach to drastically reduce the potential for HIV to develop resistance to therapies. Using its proprietary mechanism- based screening (MBS) and HIV cellular assays, Sirga has successfully identified an initial set of bioactive hits that block HIV recruitment of human tRNA3Lys (htRNA3Lys), that primes reverse transcription-a critical step in viral replication. These nontoxic hits to cells at doses effective against HIV, provide an opportunity to discover a novel class of HIV drug. HIV's dedication to htRNA3Lys is a strong validation that htRNA3Lys and its recruitment by viral proteins are critical targets for which drug resistance may be difficult to achieve. During Phase I Sirga will focus on translating hits into validated and more-potent leads. In Aim 1, Sirga will use in silico and organic synthesis approaches to identify and select series of drug-like hits having higher affinity (kd in nM range) with htRNA3Lys as measured in our MBS assay. In Aim 2, Sirga will identify two to three tractable hit series having an optimum effective non-toxic concentration in the nM range in cellular assays. In Aim 3, the mode of action (MOA) and specificity of Sirga's leads to unambiguously target tRNA3Lys with high affinity will be confirmed. Phase I success will lead to a Phase II project focused on optimization/pre-clinical testing of the lead candidate; discussions with potential Phase III partners are under way. To supplement the Sirga R&D team's collective 107 years of expertise in RNA chemistry and early-stage drug discovery-including PI Dr. Vendeix's 13-year and consultant Dr. Agris' 40-year tenures in this field-Sirga has enlisted the support of Dr. Nelson of the UNC's Center for Aids Research (CFAR), a leading virology expert in HIV/AIDS. Also on the team is Mr. Janzen, a high-throughput screening (HTS) assay-development expert. The medicinal chemistry effort is supported by Dr. Frye, Director of UNC's Center for Integrative Chemical Biology and Drug Discovery and former GSK Worldwide Vice President of Discovery Medicinal Chemistry. Dr. Toone will be engaged in the physical organic chemistry of the small molecules. Dr. Dmitri Kireev, with his combined 20 years of industrial and academic drug-discovery experience, will support the computational approach.